Studies from our laboratory and others have shown that relatively minor aversive events such as academic examinations can have a significant impact on cellular immunity. Although it is generally presumed that the immune system is the central mediating link between stressful events and an increased incidence of infectious disease, very few studies have simultaneously shown a relationship between psychological distress, altered immunity, and health changes. We have shown that the medical student model using exam- ination stress is a reliable model psychological measuring changes, particularly in the cellular immune response as it relates to psychological stress. We now plan to use this model to study mechanisms underlying the central nervous system (CNS)- endocrineimmune axis. We will incorporate detailed immunological and endocrine studies as part of the program project grant proposal, allowing us to explore the effects of psychological stress on the immune system and endocrine systems in humans, and the interaction between the two systems under controlled conditions. There are two phases in this project. Initially, we will follow two separate groups of 20 medical students (total n = 40) over one academic year. We will use selected immunological assays, based on our previous studies on academic stress. These measures will include natural killer cell activity, the blastogenic response to two mitogens, phytohemagglutinin, and concanavalin A, the production of gamma interferon, and reactivation of latent Epstein-Barr virus by measuring changes in antibody titers (as a measure of cellular immunity), and endocrine assays (in collaboration with Dr. W. Malarkey, Project No. 3) to study mechanisms that we hypothesize underlie the changes in cellular immunity previously observed by our laboratory and others. We predict that medical students will show cyclical downward changes in immune function during examination periods. When this phase is completed, we will examine other aspects of cellular immunity that nave not been examined to date. Using the medical student model, we will explore the mechanisms whereby psychological stress down- regulates the immune response. The focus of this series of studies will be macrophage function, T-cell immunity, and gene expression/production in lymphocytes of two "stress hormones," prolactin and growth hormone. We will measure the production of interleukin-l (a monokine) by macrophages, HLA-DR, HLA-DQ, and HLA- DP expression, and macrophage mediated cell killing. Detailed hormonal studies performed in Project 3 will interface with these studies, providing a means to study the CNS-endocrine-immune axis.